This material may be protected by copyright. Personal, including educational and academic, use of this material is without restriction but acknowledgement of the University of Nevada, Las Vegas, University Libraries is requested whether the use is oral, web or in print. Commercial use of any portion of this material requires permission from the ...

This material may be protected by copyright. Personal, including educational and academic, use of this material is without restriction but acknowledgement of the University of Nevada, Las Vegas, University Libraries is requested whether the use is oral, web or in print. Commercial use of any portion of this material requires permission from the University Libraries. For further information please contact Digital Collections: http://digital.library.unlv.edu/contact Minimize

The innate immune system is a highly sensitive organ of perception sensing any cell stress and tissue injury. Its major type of response to all potential inciting and dangerous challenges is inflammation and tissue repair and, if needed, induction of a supportive adaptive immune response, the aim always being to maintain homeostasis. However, al...

The innate immune system is a highly sensitive organ of perception sensing any cell stress and tissue injury. Its major type of response to all potential inciting and dangerous challenges is inflammation and tissue repair and, if needed, induction of a supportive adaptive immune response, the aim always being to maintain homeostasis. However, although initially beneficial, innate immunity-mediated, protection-intended repair processes become pathogenic when they are exaggerated and uncontrolled, resulting in permanent fibrosis which replaces atrophic or dying tissue and may lead to organ dysfunction or even failure. In this sense, atherosclerosis and organ fibrosis reflect classical disorders caused by an overreacting innate immune system. Strikingly, these two pathologies dominate the development of chronic allograft dysfunction as the main clinical problem still left in transplantation medicine. Growing evidence suggests that acute and chronic allograft injuries, including alloimmune-, isoimmune-, nonimmune-, and infection-mediated insults, not only lead to cell death-associated graft atrophy but also activate the innate immune system which, over time, leads to uncontrolled intragraft fibrogenesis, thereby compromising allograft function. Acute and chronic allograft injuries lead to induction of damage-associated molecular patterns (DAMPs) which, after recognition by pattern recognition receptors, activate cells of the innate immune system such as donor-derived intragraft fibroblasts and vascular cells as well as recipient-derived graft-invading macrophages and leukocytes. It is mainly the orchestrated action and function of these cells that slowly but steadily metamorphose the originally life-saving allograft into a poorly functioning organ of marginal viability. Minimize

There is increasing interest by physicians in the impact of the innate immune system on human diseases. In particular, the role of the molecules that initiate and amplify innate immune pathways, namely damage-associated molecular patterns (DAMPs), is of interest as these molecules are involved in the pathogenesis of many human disorders. The fir...

There is increasing interest by physicians in the impact of the innate immune system on human diseases. In particular, the role of the molecules that initiate and amplify innate immune pathways, namely damage-associated molecular patterns (DAMPs), is of interest as these molecules are involved in the pathogenesis of many human disorders. The first part of this review identifies five classes of cell stress/tissue injury-induced DAMPs that are sensed by various recognition receptor-bearing cells of the innate immune system, thereby mounting inflammation, promoting apoptosis and shaping adaptive immune responses. The DAMPs activate and orchestrate several innate immune machineries, including inflammasomes and the unfolded protein response that synergistically operates to induce inflammatory, metabolic and adaptive immune pathologies. Two examples of autoimmune diseases are discussed as they represent a typical paradigm of the intimate interplay between innate and adaptive immune responses. Minimize

This article briefly describes our own experience with the proven demonstration of heat shock protein 70 (HSP70) in reperfused renal allografts from brain-dead donors and reflects about its potential role as a typical damage-associated molecular pattern (DAMP) in the setting of innate alloimmunity. In fact, our group was able to demonstrate a dr...

This article briefly describes our own experience with the proven demonstration of heat shock protein 70 (HSP70) in reperfused renal allografts from brain-dead donors and reflects about its potential role as a typical damage-associated molecular pattern (DAMP) in the setting of innate alloimmunity. In fact, our group was able to demonstrate a dramatic up-regulation of HSP70 expression after postischemic reperfusion of renal allografts. Of note, up-regulation of this stress protein expression, although to a lesser extent, was already observed after cold storage of the organ indicating that this molecule is already induced in the stressed organism of a brain-dead donor. However, whether or not the dramatic up-regulation of HSP70 expression contributes to mounting an innate alloimmune response cannot be judged in view of these clinical findings. Nevertheless, HSP70, since generated in association with postischemic reperfusion-induced allograft injury, can be called a typical DAMP – as can every molecule be termed a DAMP that is generated in association with any stressful tissue injury regardless of its final positive or negative regulatory function within the innate immune response elicited by it. In fact, as we discuss in this article, the context-dependent, even contradistinctive activities of HSP70 reflect the biological phenomenon that, throughout evolution, mammals have developed an elaborate network of positive and negative regulatory mechanisms, which provide balance between defensive and protective measures against unwarranted destruction of the host. In this sense, up-regulated expression of HSP70 in an injured allograft might reflect a pure protective response against the severe oxidative injury of a reperfused donor organ. On the other hand, up-regulated expression of this stress protein in an injured allograft might reflect a (futile) attempt of the innate immune system to restore homeostasis with the aim to eliminate the “unwanted foreign allograft invader” by contributing to development of an adaptive alloimmune response. However, this adaptive immune response against donor histocompatibility alloantigens – in its evolutionary sense aimed to restore homeostasis – is by no means protective from a recipient’s view point but tragically ends up with allograft rejection. Indeed: in this sense, allograft rejection is the result of a fateful confusion by the immune system of danger and benefit! Minimize

Current notions in immunology hold that not only pathogen-mediated tissue injury but any injury activates the innate immune system. In principle, this evolutionarily highly conserved, rapid first-line defense system responds to pathogen-induced injury with the creation of infectious inflammation, and non-pathogen-induced tissue injury with ‘ster...

Current notions in immunology hold that not only pathogen-mediated tissue injury but any injury activates the innate immune system. In principle, this evolutionarily highly conserved, rapid first-line defense system responds to pathogen-induced injury with the creation of infectious inflammation, and non-pathogen-induced tissue injury with ‘sterile’ tissue inflammation. In this review, evidence has been collected in support of the notion that the transfusion-related acute lung injury induces a ‘sterile’ inflammation in the lung of transfused patients in terms of an acute innate inflammatory disease. The inflammatory response is mediated by the patient's innate immune cells including lung-passing neutrophils and pulmonary endothelial cells, which are equipped with pattern recognition receptors. These receptors are able to sense injury-induced, damage-associated molecular patterns (DAMPs) generated during collection, processing, and storage of blood/blood components. The recognition process leads to activation of these innate cells. A critical role for a protein complex known as the NLRP3 inflammasome has been suggested to be at the center of such a scenario. This complex undergoes an initial ‘priming’ step mediated by 1 class of DAMPs and then an ‘activating’ step mediated by another class of DAMPs to activate interleukin-1beta and interleukin-18. These 2 cytokines then promote, via transactivation, the formation of lung inflammation. Minimize

Multicellular organisms suffer injury and serve as hosts for microorganisms. Therefore, they require mechanisms to detect injury and to distinguish the self from the non-self and the harmless non-self (microbial mutualists and commensals) from the detrimental non-self (pathogens). Danger signals are “damage-associated molecular patterns” (DAMPs)...

Multicellular organisms suffer injury and serve as hosts for microorganisms. Therefore, they require mechanisms to detect injury and to distinguish the self from the non-self and the harmless non-self (microbial mutualists and commensals) from the detrimental non-self (pathogens). Danger signals are “damage-associated molecular patterns” (DAMPs) that are released from the disrupted host tissue or exposed on stressed cells. Seemingly ubiquitous DAMPs are extracellular ATP or extracellular DNA, fragmented cell walls or extracellular matrices, and many other types of delocalized molecules and fragments of macromolecules that are released when pre-existing precursors come into contact with enzymes from which they are separated in the intact cell. Any kind of these DAMPs enable damaged-self recognition, inform the host on tissue disruption, initiate processes aimed at restoring homeostasis, such as sealing the wound, and prepare the adjacent tissues for the perception of invaders. In mammals, antigen-processing and -presenting cells such as dendritic cells mature to immunostimulatory cells after the perception of DAMPs, prime naïve T-cells and elicit a specific adaptive T-/B-cell immune response. We discuss molecules that serve as DAMPs in multiple organisms and their perception by pattern recognition receptors (PRRs). Ca2+-fluxes, membrane depolarization, the liberation of reactive oxygen species and mitogen-activated protein kinase (MAPK) signaling cascades are the ubiquitous molecular mechanisms that act downstream of the PRRs in organisms across the tree of life. Damaged-self recognition contains both homologous and analogous elements and is likely to have evolved in all eukaryotic kingdoms, because all organisms found the same solutions for the same problem: damage must be recognized without depending on enemy-derived molecules and responses to the non-self must be directed specifically against detrimental invaders. Minimize

In 2004 a design engineer on-line mentoring tool was developed and implemented The purpose of the tool was to assist senior engineers mentoring new engineers to the INDOT design process and improve their technical competency. This approach saves senior engineers time while developing a consistent mentoring approach and standardizing technical kn...

In 2004 a design engineer on-line mentoring tool was developed and implemented The purpose of the tool was to assist senior engineers mentoring new engineers to the INDOT design process and improve their technical competency. This approach saves senior engineers time while developing a consistent mentoring approach and standardizing technical knowledge in road and bridge design. It is a self-guided tool that utilizes multi-media and web-based technologies, trains engineers in the design process and provides resources to use for developing plans and specifications. Available resources include INDOT design practices, design standards, design memos, specification and construction standards, procedures, and check lists. When this tool was developed the Design Manual was under development. Therefore, the tool could not link to the Design Manual but to excerpted sections extracted from the Manual. Now active linking to this Manual is possible. Additionally other resources used in the design process: design standards, design memos, design procedures and checklists should be accessible in the various topics. These current resources have also influenced the technical content for the current 12 topics. An upgrade was performed to deal with these needs and to make the tool a living one, that is where future revisions in resources can be incorporated without a major overhaul to the application. Minimize